Abstract
Muscle atrophy can be caused by unloading stress such as microgravity environments or cast immobilization. Therapies for such disuse muscle atrophy and their underlying mechanisms are incompletely understood. Here, we investigated the therapeutic effects of local vibration stimulation on immobilization-induced skeletal muscle atrophy. A rat model was made by placing the left hindlimb in a cast for 1 week, leading to oxidative myofiber atrophy without myopathic changes in soleus skeletal muscle. Vibration stimulus (90 Hz, 15 min) to the plantar fascia of the atrophic hindlimb was performed once a day using a hand-held vibration massager after removal of a cast at the end of the immobilization period. After 2 weeks, rats were dissected, and quantitative analysis of the cross-sectional areas of soleus myofibers was performed. The results revealed that vibration induced significant recovery from disuse muscle atrophy, compared with untreated immobilized samples. Furthermore, vibration treatment suppressed the fiber transition from slow to fast fiber types compared with vibration-untreated immobilized samples. Western blotting analyses of mechanical stress-induced factors revealed that the expression of mechano-growth factor (MGF), systemic insulin-like growth factor I, and the mechanotransduction protein, Yes-associated protein 1 (YAP1), was decreased in untreated immobilized soleus muscle, whereas vibration stimulation restored their expression. No change in the level of phosphorylation of YAP1Ser127 was observed, leading to no change in p-YAP1/YAP1 ratio in vibration-treated immobilized soleus muscle. The results indicate that vibration stimulus is effective to restore immobilization-induced inactivation of YAP1 pathway. Phosphorylation of ERK 1/2, but not AKT, was enhanced in vibration-treated immobilized soleus muscle. Furthermore, vibration stimuli restored immobilization-induced downregulation of the paired box transcription factor, PAX7, a critical factor for regenerative myogenesis in muscle satellite cells. Our results indicate that cyclic vibration stimuli are effective in activating satellite cells and facilitate recovery from immobilization-induced oxidative myofiber atrophy through upregulation of MGF and YAP1.
Highlights
Unloading stress, such as that experienced in the microgravity of space flight or during cast immobilization, induces skeletal muscle atrophy
We demonstrate for the first time that local vibration stimulation of the plantar fascia can facilitate recovery from immobilization-induced soleus skeletal muscle atrophy in rats and suppress the fiber transition from slow oxidative to fast glycolytic fiber types (Figures 5A–G)
Immunohistochemistry and western blotting analyses demonstrated that vibration stimulation of the plantar fascia upregulates mechanogrowth factor (MGF), systemic IGF-Ia, and Yes-associated protein 1 (YAP1) expression, without alteration of phosphorylated-YAP1Serine127 levels (Figure 6)
Summary
Unloading stress, such as that experienced in the microgravity of space flight or during cast immobilization, induces skeletal muscle atrophy. Limb immobilization can be modeled in rats using a cast (Hamaue et al, 2015) or by hindlimb suspension (Thomason and Booth, 1990), which causes severe atrophy of soleus skeletal muscle, consisting of slow twitch oxidative fibers. Stress-induced fiber transition, from slow oxidative to fast glycolytic fiber types, has been reported in unloading models such as the environment of spaceflight/ microgravity and hindlimb suspension (Baldwin et al, 2013); the mechanisms underlying different fiber type atrophy, fiber transition, and the regenerative processes remain unknown, some associated factors such as mechano growth factor (MGF), systemic variant of insulin-like growth factor (IGF-I), Hippo pathway, and muscle stem cells have been reported (Goldspink, 1999; Kandalla et al, 2011; Brooks and Myburgh, 2014; Gnimassou et al, 2017; Fukada, 2018)
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